Fever, also known as pyrexia and febrile response,[6] is defined as
having a temperature above the normal range due to an increase in the
body's temperature set-point.[4][5] There is not a single agreed-upon
upper limit for normal temperature with sources using values between
37.5 and 38.3 °C (99.5 and 100.9 °F).[6][7] The increase
in set-point triggers increased muscle contractions and causes a
feeling of cold.[1] This results in greater heat production and
efforts to conserve heat.[2] When the set-point temperature returns to
normal, a person feels hot, becomes flushed, and may begin to
sweat.[2] Rarely a fever may trigger a febrile seizure.[3] This is
more common in young children.[3] Fevers do not typically go higher
than 41 to 42 °C (105.8 to 107.6 °F).[5]
A fever can be caused by many medical conditions ranging from non
serious to life threatening.[11] This includes viral, bacterial and
parasitic infections such as the common cold, urinary tract
infections, meningitis, malaria and appendicitis among others.[11]
Non-infectious causes include vasculitis, deep vein thrombosis, side
effects of medication, and cancer among others.[11] It differs from
hyperthermia, in that hyperthermia is an increase in body temperature
over the temperature set-point, due to either too much heat production
or not enough heat loss.[6]
Treatment to reduce fever is generally not required.[1][8] Treatment
of associated pain and inflammation, however, may be useful and help a
person rest.[8] Medications such as ibuprofen or paracetamol
(acetaminophen) may help with this as well as lower temperature.[8][9]
Measures such as putting a cool damp cloth on the forehead and having
a slightly warm bath are not useful and may simply make a person more
uncomfortable.[8] Children younger than three months require medical
attention, as might people with serious medical problems such as a
compromised immune system or people with other symptoms.[12]
HyperthermiaHyperthermia does require treatment.[1]
FeverFever is one of the most common medical signs.[1] It is part of about
30% of healthcare visits by children[1] and occurs in up to 75% of
adults who are seriously sick.[10] While fever is a useful defense
mechanism, treating fever does not appear to worsen outcomes.[13][14]
FeverFever is viewed with greater concern by parents and healthcare
professionals than it usually deserves, a phenomenon known as fever
phobia.[1]

Note: The difference between fever and hyperthermia is the underlying
mechanism. Different sources have different cut-offs for fever,
hyperthermia and hyperpyrexia.

v
t
e

A wide range for normal temperatures has been found.[7] Central
temperatures, such as rectal temperatures, are more accurate than
peripheral temperatures.[20]
FeverFever is generally agreed to be present
if the elevated temperature is caused by a raised set point and:

In healthy adult men and women, the range of normal, healthy
temperatures for oral temperature is 33.2–38.2 °C
(91.8–100.8 °F), for rectal it is 34.4–37.8 °C
(93.9–100.0 °F), for tympanic membrane (the ear drum) it is
35.4–37.8 °C (95.7–100.0 °F), and for axillary (the
armpit) it is 35.5–37.0 °C (95.9–98.6 °F).[22]
Harrison's principles of internal medicine defines a fever as a
morning oral temperature of >37.2 °C (>98.9 °F) or
an afternoon oral temperature of >37.7 °C (>99.9 °F)
while the normal daily temperature variation is typically 0.5 °C
(0.9 °F).[23]
Normal body temperatures vary depending on many factors, including
age, sex, time of day, ambient temperature, activity level, and more.
A raised temperature is not always a fever. For example, the
temperature of a healthy person rises when he or she exercises, but
this is not considered a fever, as the set-point is normal. On the
other hand, a "normal" temperature may be a fever, if it is unusually
high for that person. For example, medically frail elderly people have
a decreased ability to generate body heat, so a "normal" temperature
of 37.3 °C (99.1 °F) may represent a clinically
significant fever.
Types[edit]

The pattern of temperature changes may occasionally hint at the
diagnosis:

Continuous fever:
TemperatureTemperature remains above normal throughout the day
and does not fluctuate more than 7002274149999999999♠1 °C in
24 hours, e.g. lobar pneumonia, typhoid, meningitis, urinary tract
infection, or typhus.
TyphoidTyphoid fever may show a specific fever pattern
(Wunderlich curve of typhoid fever), with a slow stepwise increase and
a high plateau. (Drops due to fever-reducing drugs are excluded.)
Intermittent fever: The temperature elevation is present only for a
certain period, later cycling back to normal, e.g. malaria, kala-azar,
pyaemia, or septicemia. Following are its types:[24]

Remittent fever:
TemperatureTemperature remains above normal throughout the day
and fluctuates more than 7002274149999999999♠1 °C in 24 hours,
e.g., infective endocarditis, brucellosis.
Pel-Ebstein fever: A specific kind of fever associated with Hodgkin's
lymphoma, being high for one week and low for the next week and so on.
However, there is some debate as to whether this pattern truly
exists.[25]

A neutropenic fever, also called febrile neutropenia, is a fever in
the absence of normal immune system function. Because of the lack of
infection-fighting neutrophils, a bacterial infection can spread
rapidly; this fever is, therefore, usually considered to require
urgent medical attention. This kind of fever is more commonly seen in
people receiving immune-suppressing chemotherapy than in apparently
healthy people.
Febricula is an old term for a low-grade fever, especially if the
cause is unknown, no other symptoms are present, and the patient
recovers fully in less than a week.[26]
Hyperpyrexia[edit]
HyperpyrexiaHyperpyrexia is an extreme elevation of body temperature which,
depending upon the source, is classified as a core body temperature
greater than or equal to 40.0 or 41.5 °C (104.0 or
106.7 °F).[27][28][29] Such a high temperature is considered a
medical emergency, as it may indicate a serious underlying condition
or lead to problems including permanent brain damage, or death.[30]
The most common cause of hyperpyrexia is an intracranial
hemorrhage.[31][29] Other possible causes include sepsis, Kawasaki
syndrome,[32] neuroleptic malignant syndrome, drug overdose, serotonin
syndrome, and thyroid storm.[30]
Infections are the most common cause of fevers, but as the temperature
rises other causes become more common.[30] Infections commonly
associated with hyperpyrexia include roseola, measles and enteroviral
infections.[32] Immediate aggressive cooling to less than
38.9 °C (102.0 °F) has been found to improve survival.[30]
HyperpyrexiaHyperpyrexia differs from hyperthermia in that in hyperpyrexia the
body's temperature regulation mechanism sets the body temperature
above the normal temperature, then generates heat to achieve this
temperature, while in hyperthermia the body temperature rises above
its set point due to an outside source.[31]
Hyperthermia[edit]
HyperthermiaHyperthermia is an example of a high temperature that is not a fever.
It occurs from a number of causes including heatstroke, neuroleptic
malignant syndrome, malignant hyperthermia, stimulants such as
substituted amphetamines and cocaine, idiosyncratic drug reactions,
and serotonin syndrome.[33][34]
Signs and symptoms[edit]

Michael Ancher, "The Sick Girl", 1882, Statens Museum for Kunst

A fever is usually accompanied by sickness behavior, which consists of
lethargy, depression, anorexia, sleepiness, hyperalgesia, and the
inability to concentrate.[35][36][37]
Differential diagnosis[edit]
FeverFever is a common symptom of many medical conditions:

Persistent fever that cannot be explained after repeated routine
clinical inquiries is called fever of unknown origin.
TeethingTeething is not a cause.[40]
Pathophysiology[edit]

Hyperthermia: Characterized on the left. Normal body temperature
(thermoregulatory set point) is shown in green, while the hyperthermic
temperature is shown in red. As can be seen, hyperthermia can be
conceptualized as an increase above the thermoregulatory set point.
Hypothermia: Characterized in the center: Normal body temperature is
shown in green, while the hypothermic temperature is shown in blue. As
can be seen, hypothermia can be conceptualized as a decrease below the
thermoregulatory set point.
Fever: Characterized on the right: Normal body temperature is shown in
green. It reads "New Normal" because the thermoregulatory set point
has risen. This has caused what was the normal body temperature (in
blue) to be considered hypothermic.

TemperatureTemperature is ultimately regulated in the hypothalamus. A trigger of
the fever, called a pyrogen, causes a release of prostaglandin E2
(PGE2). PGE2 then in turn acts on the hypothalamus, which generates a
systemic response back to the rest of the body, causing heat-creating
effects to match a new temperature level.
In many respects, the hypothalamus works like a thermostat.[41] When
the set point is raised, the body increases its temperature through
both active generation of heat and retention of heat. Peripheral
vasoconstriction both reduces heat loss through the skin and causes
the person to feel cold.
NorepinephrineNorepinephrine increases thermogenesis in
brown adipose tissue, and acetylcholine stimulates muscle to raise
metabolic rate.[42] If these measures are insufficient to make the
blood temperature in the brain match the new set point in the
hypothalamus, then shivering begins in order to use muscle movements
to produce more heat. When the hypothalamic set point moves back to
baseline either spontaneously or with medication, the reverse of these
processes (vasodilation, end of shivering and nonshivering heat
production) and sweating are used to cool the body to the new, lower
setting.
This contrasts with hyperthermia, in which the normal setting remains,
and the body overheats through undesirable retention of excess heat or
over-production of heat.[41]
HyperthermiaHyperthermia is usually the result of an
excessively hot environment (heat stroke) or an adverse reaction to
drugs.
FeverFever can be differentiated from hyperthermia by the
circumstances surrounding it and its response to anti-pyretic
medications.
Pyrogens[edit]
A pyrogen is a substance that induces fever. These can be either
internal (endogenous) or external (exogenous) to the body. The
bacterial substance lipopolysaccharide (LPS), present in the cell wall
of gram-negative bacteria,[43] is an example of an exogenous pyrogen.
Pyrogenicity can vary: In extreme examples, some bacterial pyrogens
known as superantigens can cause rapid and dangerous fevers.
Depyrogenation may be achieved through filtration, distillation,
chromatography, or inactivation.
Endogenous[edit]
In essence, all endogenous pyrogens are cytokines, molecules that are
a part of the immune system. They are produced by activated immune
cells and cause the increase in the thermoregulatory set point in the
hypothalamus. Major endogenous pyrogens are interleukin 1 (α and
β)[44] and interleukin 6 (IL-6). Minor endogenous pyrogens include
interleukin-8, tumor necrosis factor-β, macrophage inflammatory
protein-α and macrophage inflammatory protein-β as well as
interferon-α, interferon-β, and interferon-γ.[44] Tumor necrosis
factor-α also acts as a pyrogen. It is mediated by interleukin 1
(IL-1) release.[45]
These cytokine factors are released into general circulation, where
they migrate to the circumventricular organs of the brain due to
easier absorption caused by the blood–brain barrier's reduced
filtration action there. The cytokine factors then bind with
endothelial receptors on vessel walls, or interact with local
microglial cells. When these cytokine factors bind, the arachidonic
acid pathway is then activated.
Exogenous[edit]
One model for the mechanism of fever caused by exogenous pyrogens
includes LPS, which is a cell wall component of gram-negative
bacteria. An immunological protein called lipopolysaccharide-binding
protein (LBP) binds to LPS. The LBP–LPS complex then binds to the
CD14CD14 receptor of a nearby macrophage. This binding results in the
synthesis and release of various endogenous cytokine factors, such as
interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis
factor-alpha. In other words, exogenous factors cause release of
endogenous factors, which, in turn, activate the arachidonic acid
pathway.[46] The highly toxic metabolism-boosting supplement
2,4-Dinitrophenol2,4-Dinitrophenol induces high body temperature via the inhibition of
ATP production by mitochondria, resulting in impairment of cellular
respiration. Instead of producing ATP, the energy of the proton
gradient is lost as heat.[47]
PGE2 release[edit]
PGE2 release comes from the arachidonic acid pathway. This pathway (as
it relates to fever), is mediated by the enzymes phospholipase A2
(PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase. These
enzymes ultimately mediate the synthesis and release of PGE2.
PGE2 is the ultimate mediator of the febrile response. The set point
temperature of the body will remain elevated until PGE2 is no longer
present. PGE2 acts on neurons in the preoptic area (POA) through the
prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA
innervate the dorsomedial hypothalamus (DMH), the rostral raphe
pallidus nucleus in the medulla oblongata (rRPa), and the
paraventricular nucleus (PVN) of the hypothalamus .
FeverFever signals sent
to the DMH and rRPa lead to stimulation of the sympathetic output
system, which evokes non-shivering thermogenesis to produce body heat
and skin vasoconstriction to decrease heat loss from the body surface.
It is presumed that the innervation from the POA to the PVN mediates
the neuroendocrine effects of fever through the pathway involving
pituitary gland and various endocrine organs.
Hypothalamus[edit]
The brain ultimately orchestrates heat effector mechanisms via the
autonomic nervous system or primary motor center for shivering. These
may be:

Increased heat production by increased muscle tone, shivering and
hormones like epinephrine (adrenaline)
Prevention of heat loss, such as vasoconstriction.

In infants, the autonomic nervous system may also activate brown
adipose tissue to produce heat (non-exercise-associated thermogenesis,
also known as non-shivering thermogenesis). Increased heart rate and
vasoconstriction contribute to increased blood pressure in fever.
Usefulness[edit]
There are arguments for and against the usefulness of fever, and the
issue is controversial.[48][49] [50] There are studies using
warm-blooded vertebrates with some suggesting that they recover more
rapidly from infections or critical illness due to fever.[51] Studies
suggest reduced mortality in bacterial infections when fever was
present.[52]
In theory, fever can aid in host defense.[48] There are certainly some
important immunological reactions that are sped up by temperature, and
some pathogens with strict temperature preferences could be
hindered.[53]
Research[54] has demonstrated that fever assists the healing process
in several important ways:

Management[edit]
FeverFever should not necessarily be treated.[56] Most people recover
without specific medical attention.[57] Although it is unpleasant,
fever rarely rises to a dangerous level even if untreated. Damage to
the brain generally does not occur until temperatures reach
42 °C (107.6 °F), and it is rare for an untreated fever to
exceed 40.6 °C (105 °F).[56] Treating fever in people with
sepsis does not affect outcomes.[58]
Conservative measures[edit]
Some limited evidence supports sponging or bathing feverish children
with tepid water.[59] The use of a fan or air conditioning may
somewhat reduce the temperature and increase comfort. If the
temperature reaches the extremely high level of hyperpyrexia,
aggressive cooling is required (generally produced mechanically via
conduction by applying numerous ice packs across most of the body or
direct submersion in ice water).[30] In general, people are advised to
keep adequately hydrated.[60] Whether increased fluid intake improves
symptoms or shortens respiratory illnesses such as the common cold is
not known.[61]
Medications[edit]
Medications that lower fevers are called antipyretics. The antipyretic
ibuprofen is effective in reducing fevers in children.[62] It is more
effective than acetaminophen (paracetamol) in children.[62] Ibuprofen
and acetaminophen may be safely used together in children with
fevers.[63][64] The efficacy of acetaminophen by itself in children
with fevers has been questioned.[65]
IbuprofenIbuprofen is also superior to
aspirin in children with fevers.[66] Additionally, aspirin is not
recommended in children and young adults (those under the age of 16 or
19 depending on the country) due to the risk of Reye's syndrome.[67]
Using both paracetamol and ibuprofen at the same time or alternating
between the two is more effective at decreasing fever than using only
paracetamol or ibuprofen.[68] It is not clear if it increases child
comfort.[68] Response or nonresponse to medications does not predict
whether or not a child has a serious illness.[69]
Epidemiology[edit]
About 5% of people who go to an emergency room have a fever.[70]
History[edit]
A number of types of fever were known as early as 460 BC to 370 BC
when
HippocratesHippocrates was practicing medicine including that due to malaria
(tertian or every 2 days and quartan or every 3 days).[71] It also
became clear around this time that fever was a symptom of disease
rather than a disease in and of itself.[71]
Society and culture[edit]
Etymology[edit]
Pyrexia is from the Greek pyr meaning fire. Febrile is from the Latin
word febris, meaning fever, and archaically known as ague.
FeverFever phobia[edit]
FeverFever phobia is the name given by medical experts to parents'
misconceptions about fever in their children. Among them, many parents
incorrectly believe that fever is a disease rather than a medical
sign, that even low fevers are harmful, and that any temperature even
briefly or slightly above the oversimplified "normal" number marked on
a thermometer is a clinically significant fever.[72] They are also
afraid of harmless side effects like febrile seizures and dramatically
overestimate the likelihood of permanent damage from typical
fevers.[72] The underlying problem, according to professor of
pediatrics Barton D. Schmitt, is "as parents we tend to suspect that
our children’s brains may melt."[73]
As a result of these misconceptions parents are anxious, give the
child fever-reducing medicine when the temperature is technically
normal or only slightly elevated, and interfere with the child's sleep
to give the child more medicine.[72]
Other animals[edit]
FeverFever is an important feature for the diagnosis of disease in domestic
animals. The body temperature of animals, which is taken rectally, is
different from one species to another. For example, a horse is said to
have a fever above 7002311483333333333♠101 °F
(7002311450000000000♠38.3 °C).[74] In species that allow the
body to have a wide range of "normal" temperatures, such as
camels,[75] it is sometimes difficult to determine a febrile stage.
FeverFever can also be behaviorally induced by invertebrates that do not
have immune-system based fever. For instance, some species of
grasshopper will thermoregulate to achieve body temperatures that are
2–5 °C higher than normal in order to inhibit the growth of
fungal pathogens such as
Beauveria bassianaBeauveria bassiana and Metarhizium
acridum.[76] Honeybee colonies are also able to induce a fever in
response to a fungal parasite Ascosphaera apis. [76]
References[edit]